1-methyl-1, 3, 5, 6, 16 estrapentaenes and a process for making them



ilnited States Patent 1-METHYL-1,3,5,6,16 ESTRAPENTAENESo-AND A PROCESSFOR MAKING THEM Carl 'Djerassi, Birmingham Mich and George Rosenk'ranz',Mexico City, Mexico, assipors 'toSyntefx SA Mexico City, Mexico, acorporation of Mexico No Drawing. 1 Application August 12, 19% ySerialNo. 528,130

Claims. (Cl. 260-39141 j The present invention relates tonovelcyclope'ntano;

phenanthrene compounds andto a novel process; for

preparingthe same. y I v More particularly, the present inventionrelates to novel steroid compounds having a l-methyl aromatictring A andan acetyl group at C-17 and to a novel process for preparing'such'compounds. The-novel compounds produced in accordance with the presentinvention are belivedlo have therapeutic value as well asbeingespecially suitable as intermediates for'the production of therapeuticcompounds.

In accordance with the present invention :it has been discovered thatprogesterone may be 'trfibrorninated to produce a novel2,6,17-tribroinoprogesteronewhich may be dehydrobrominatedto produce anovel A -pregnatetraene-3,20 dione.

Itjhas further been discovered that the tetraerie thus produced may besubjected to a dienone-phenol re-o arrangement to produce novel1-methyl-3-hydroxy-l7- acetyl-r A -l -e'strapentaene and/or acyl;derivatives thereof which may be hydrogenated'to produce novel- 1methyl-B-hydroxy-l7-acetylrA -estratriene compounds.

The A 4 -pregnatetraene may ialsobe produced. by

dibromination of 16-dehydroprogesterone followed by refiuxing withcollidine. V e v t The final compound of the process ot the presentinvent, i.e. 1-methyl-3-hydroxy-1:7-acetyl-Al -estratriene is a valuableintermediate for the production of the active progestational hormonel-methyl-l9-nor-progesterone.

-Upon' treatment of the l-methyl-3-hydroxy-l7a-acetyl- A -estratrienewith methyl sulfate thereis'prepared the corresponding 3-metho-Xyderivative.-. Treatment ofthis .methoxy derivative with lithium metal inliquid ammohis; then produced 1-rnethyl-3 methoxy-19-nor-A Q pregnadienZOi-OI. Hydrolysis and rearrangement of this compound. in (acid mediumgave .1-met-hyl-l9-nonA pregnen-2O- ol-3 one which was: then oxidizedwith chr omic acid to 1-methyl-1Q-nor-Ai-pregnen-Ql,ZO-dione (1-methyl-1finer-progesterone).

Thefinal compound of ,the process of the present in- J vention can alsobeused tozmalce the estrogenic hormone l-methyl estradiol' since the-3-acetate' thereof' upon deg- 1 -radation with perbenzoi'c acid givesthe diacetate of "1- 7 methyl estradiol which may be conventionallysaponified; v exiiipli- The process of the present inve I tion may 7'-"'-The same tetraene-a'could also be. producedz'b dibio-L; minating 16-dehydr9progesterohe and tliereaftei 'rfluxiiig V a Dehydrobrqniinatlon7 2,925,428 Patented Feb. 16, 1960 ice . Heat 7 Acetic Anhydride Op-toluenesulfonic Aeid- Dibromination tollowedhy DchydrobrominationHydrogenation 3'0 7 In the foregoing equations R represents the residueof acetic acid'or in the event propionic'acid is used'fo'r the ofpropionic acid; H d The process maybe carried out in general by treatingprogesterone suspended in a'* suitable solvent preferably anethersolventas for exampleethyl ether with 3 equivalentsjof 'bromineat a lowtemperature, i.e. temperatures from 0-C.-to 15? C; The cold suspensionis first treated with affevvj drops of hydrogen bromide acetic acid"solution and thereafter the'bromine dissolved in glacial acetic acid isslowly add'ed. When all of the bromine had been solution. After standingan additional period crystals of 2,6,17-tribromoprogesterone weredeposited. The filtrate was relwashed with water, dried; andconcentrated to produces second crop" of' crystals. The crude 2 ,6;17-tribromoprogesterone; could be: recrystallized from v meth anol andchloroform to produce the final pure product. TAlthough"'glacial aceticacid has been described as the preferredsolvent for the'bromine, otherlower fatty acids can, be-used,--as for example glacialpropionic'acid.The tribromo' compound then can be dehydrobrominof time fs'ufl'lcient toremove 3- mols'. ofshydrogen bromide.

removedbyq: can be isolated,

t-he bromination product with collidine.

The tetraene produced; as hereinbefore set forth, can

p-tolueiiesu lfonic;acid na a aieerj propiohic anh on a stear'n' bathfor a suitable periodoftime; a

amplefivehouis; V g I V g The 'reac'tion' mixture was the'ncooled and th'djr 'ide hydrolyzed with water. The produ dienone-phenol rearrangementit may represent the residue added it was noted'that all ofthe solidhad'gone into V atedby frefluxing'the same with collidinefora period tTherea'fter ethy -ac'et'at'e" ,was a'dded and theco'llidin'e V, as ngwithidihiteacid, The produce-the'n g as for: example by' evaporatiomchroma- "togrfaphing: on "alumina"; and elution with; for-- example,

r methaho then'producedj a tetra e ibeli'eved thenbesubjected.toga'dienonegphenol rearrangement as 'above outlined by heating a mixture ofthe tetraene withe of 2,6,l7-tribromoprogesterone The pentaene thusprepared was hydrogenated by treatment with hydrogen while dissolved ina suitable solvent,

as for example ethyl acetate, in the presence of a pa1ladium-on-charcoalcatalyst. 2 mols of hydrogen were ab sorbed to produce, after filtrationof the catalyst and evaporation of the solvent to dryness and finaltrituration of the residue with hexane, 1-methyl-3acetoxy-17acetyl- A-estratriene. The 3-acetate thus produced or the benzoate which could besimilarly produced by hydrogenation of the benzoate could then besaponified with alcoholic potassium hydroxide solution to produce thephenol l methyl 3 hydroxy 17 acetyl 1,3,5- estratriene. Similarly,1-rnethyl-3-hydroxy17-acetyl A -estrapentaene could be obtained bysodium bicarbonate saponification of the equivalent acetate.

The following specific examples serve to illustrate the presentinvention but are not intended to limit the same:

EXAMPLE I Tribromination of progesterone An ice-cold suspension of g. ofprogesterone in 350 cc. of ether was treated with 3 drops of hydrogenbromide-acetic acid solution followed by slow addition of a solution of15.28 g. of bromine in 150 cc. of glacial acetic acid. At the end of theaddition, all of the solid had gone into solution and after anadditional one-half hour 65 g. of colorless crystals, with a meltingpoint of 173-175 C. (decomposition) were collected. The filtrate waswashed well with water, dried and concentrated whereupon a second crop(3.8 g.) of solid, with a melting point of 170173 C. (decomposition) wasobtained, raising the yield to 59%. The analytical sample was obtainedfrom methanol-chloroform with a melting point of 174-176 C.(decomposition) [a] +2.3, ultraviolet maximum at 250 III/.4, log 6 4.21.

Anallysis.-Calculated for C21H2'102Br3: C, 45.73; H,

EXAMPLE II A -pregnatetraene-3,20-dione.-Fr0m tribromoprogesterone 10 g.of the tribromo derivative of Example .I were refluxed with 40 cc. ofcollidine for 30 minutes resulting in the loss of 3 mols of hydrogenbromide (11.3 g. of collidine hydrobromide). After addition of ethylacetate,

the collidine was removed by washing .with dilute acid and they productwas isolated by evaporation, chromatographing on alumina and elutionwith benzene. Recrystallization from acetone or methanol affordedcolorless plates (2.1 g., 37%) of the. tetraene with a melting at 234my. (log e 4.34) and 298 my. (log 6 4.19,).

Analysis.--Calculated for C H O C, 81.78; H, 7.84. Found: C, 81.77; H,7.80.

EXAMPLE III I From 16-dehydr0pr0gesterone V 16-dehydroprogesterone (6.2g.) was dibrominated exactly as described for the above tribromination,but

since the product crystallized very poorly, the ether-acetic solutionwas washed very well with water, the ether evaporated and residuerefluxed directly with collidine. A work-up similar to Example II gave1.17-1.57 (19- 4 25% over-all yield based on 16-dehydroprogesterone of A-pregnatetraene-3,20-dione (found: C, 81.66; H, 7.50) with a meltingpoint of 238-240 C., undepressed on admixture with a specimen preparedaccording to Example II; the rotations and ultraviolet absorptionspectra were identical.

EXAMPLE IV Dienone-pher'tol rearrangement of A -pregnatetraene-3,20-di0ne A solution of 1.40 g. of the tetraenedione of Examples II andIII and 0.4 g. of p-toluenesulfonic, acid in 50 cc. of acetic anhydridewas heated on the steam bath for four and one-half hours, then cooledand the anhydride hydrolyzed with water. The product was extracted withether, washed free of acid dried and evaporated. Crystallization wasinduced by trituration with ether-hexane;

yield, 0.81 g. (51%), with a melting point of 1l9126 C. Additionalmaterial was isolated from the motherliquors via'the insoluble benzoate(Example V). Repeated crystallization from ether-hexane and high-vacuumsublimation ,led to practically colorless crystals of 1-methyl-3-acetoxy-17-acetyl-A -estrapentaene with a melting point of128130 C., [oz] 100, ultraviolet maxima at 224 m (log 6 4.53) and 230 mu(loge 4.51) and minimum at 226 m (log a 4.50).

Analysis.Calculated for C H O C, 78.82; H, 7.48.

Found: C, 78.81; H, 7.62.

EXAMPLEV The filtrate from the first crop of acetate of Example -IV wassaponified by boiling for one hour with 350 mg; 'of sodium bicarbonate,15cc. of ethanol and 3.5 cc. of-

water and the resulting oil was benoxylated with pyridine-benzoylchloride. Crystallization from methanol afiorded an additional 0.26 g.(14%) of 1-methyl-3- -b'enzoyloxy-l7-acetyl-A -estrapentaene with amelting point of 200203 C. The analytical sample crystallized as needleswith a melting point of 210212 C., [a] -101.

Analysis.--Calculated for C ,;H O C, 81.52; H, 6.84.

. Found: C, 81.55; H, 6.83.

4.93; Br, 43.52. Found: C, 45.93; H, 5.08; Br, 44.02.-

.point of 239240 C., [a] 112, ultraviolet maxima EXAMPLE VI 1 methyl 3 ahydroxy 17 acetyl A -estrapentaene was obtained by sodium bicarbonatesaponification of the pure acetate of Example IV and recrystallized'from hexane-acetone; melting point 187-188.5 C., [a] 10l.4, ultravioletmaxima at 228 mp. (log a 4.53), 266 m (log e 3.91, and 306 m (log 63.25).-

vAnalysisa-Calculated for C H O C, 81.78; H, 7.84.

Found: C, 81.94; H, 8.11.

EXAMPLE VII 1-methyl-3-acet0xy-17-ace1tyl-A -estrazriene A solution of0.33 g. of the acetate of Example IV in 20cc. of ethyl acetate absorbedtwo mols of hydrogen in forty-five minutes inthe presence of mg. of 5%palladium-on-charcoal catalyst. Filtrationof the catalyst,

evaporationof the solvent to dryness and trituration of the residue withhexane gave 0.31 g. (81%) of l-rnethyl- 3-acetoxy-17-acetyl-A-estratriene with a meltingpoint of 128-130 C. The analytical sample wasonce recrystallized and then sublimed in high vacuum, melting point 129-131 C., ultraviolet maximum at 268 m (log a 2.59) and minimum at 252 my(log 6 2.42) typical of a phenolic acetate. 7

Analysis.-Calculated for C H O C, 77.93; H, 8.53. Found: C, 78.14; H,8.75.

EXAMPLE VIII 1-methyl-3-benzoyloxy-17-acetyl-A -estratriene was obtainedby the procedure of Example VII by hydrogenation of the benzoate ofExample V and crystallized from my. (log 6 2.49).-.

EXAMPLE ix 2% methanolic potassium hydroxide solution followed by of250-2s1;5 ,c., [a] +200 (dioxane), ultraviolet maximum at 284 my (log s3.31) and minimum at 252 Analysis.Calculated for 0, 14,50 0, 80.73; H,9.03.

Found: C, 80.60; H, 9.02.

The present application is a continuation-in-part of application SerialNo. 183,302, filed September 5, 1950,

I now abandoned.

We claim: t

1. A process for the production of a l-methyl-B-acyloxy-17-acetyl-A-estrapentaene selected from p the group consisting of1-methyl-3-acetoxy-17-acetyl-A1- estrapentaene and1-methyl-3-propionoxy-17-acetyl- A -estrapentaene which comprisestreating progesterone with 3 equivalents of bromine at low temperature.in the presence of a lower fatty acid to producev2,6,l7-

tribromoprogesterone, dehydrobrominating and tribromoprogesterone. toproduce A5 -pregnatetraene,20- dione with collidine and heating saiddione with an acid anhydride selected from the group'consisting ofacetic anhydride and propionic anhydride in the presence ofptoluenesulfonic acid. Y

ethyl acetate ascolorless needles witha melting of a I r Saponificationof the benzoate of Example VIII with 2. A process for the production ofa 1-methyl-3-acyl--- oxy-17-acetyl-A -estratriene*selected from thegroup consisting of li-methyl-S-acetoxy-17-acety1-A -?'-estratriv v tene and 1-methyl-3-propionoxy-17-acetyl-A -estratriene, Anzlysis.Calculatedfor,C H O3i C, 80.73; H, 7.7 5. 7

Found: C 80.74;H, 7.96. J p 1 s which comprises hydrogenating acorresponding l-methyl- "hydrogen is absorbed.

' '3. A l-methyl-17-acety1-A -estrapentaenecom pound having thefollowing structural formula:

5 i l CHi wherein R is selected from the group consisting of hydm' gen,the residues of lower fatty acids and benzoic acid.

4. 1-methyl-3-acetoxy-17-acetyl-A -estrapentaene. V 5. ,1 methyl- 3benzoyloxy 17 acetyl A estrapentaene; t

References Cited inthe' file of this patent UNITED STATES PATENTS RubinApr. 5, 1955

1. A PROCESS FOR THE PRODUCTION OF A1-METHYL-3-ACYLOXY-17-ACETYL-$1,3,5,6,15-ESTRAPENTAENE SELECTED FROM THEGROUP CONSISTING OF1-METHYL-3-ACETOXY-17-ACETYL-$1,3,5,6,16ESTRAPENTAENE AND1-METHYL-3-PROPIONOXY-17-ACETYL$1,3,5,6,16-ESTRAPENTAENE WHICH COMPRISESTREATING PROGESTERONE WITH 3 EQUIVALENTS OF BROMINE AT LOW TEMPERATUREIN THE PRESENCE OF A LOWER FATTY ACID TO PRODUCE2,6,17TRIBROMOPROGESTERONE, DEHYDROBROMINATING AND TRIBROMOPROGESTERONETO PRODUCE $1,4,6,16-PREGNATETRAENE-3,20DIONE WITH COLLIDINE AND HEATINGSAID DIONE WITH AN ACID ANHYDRIDE SELECTED FROM THE GROUP CONSISTING OFACETIC ANHYDRIDE AND PROPIONIC ANHYDRIDE IN THE PRESENCE OFPTOLUENESULFONIC ACID.
 3. A1-METHYL-17-ACETHYL-$1,3,5,6,16-ESTRAPENTAENE COMPOUND HAVING THEFOLLOWING STRUCTURAL FORMULA: